This invention relates to inhibition of acute rejection after organ transplantation.
Although transplantation of organs is becoming commonplace, rejection of the donated organ by the patient remains a serious problem. Except for cases of organ donation between identical twins or the special instance of transplantation in individuals with severe combined immunodeficiency disease, all transplant recipients currently require an immunosuppressive regimen to prevent rejection. Although these immunosuppressive drugs are administered in an attempt to prevent rejection, they also suppress the body's defenses against infection. Thus, transplantation requires a continued effort to induce acceptance of the graft without paralyzing the body's immune system.
Various regimens in use employ one or more of the following agents or therapies: (1) cortico-steroids, such as prednisone; (2) cytotoxic drugs, such as azathioprine and cyclophosphamide; (3) x-ray irradiation therapy; (4) anti-lymphocyte and anti-thymocyte globulins; (5) cyclosporine; and (6) monoclonal antibodies such as OKT3, which reacts specifically with the CD3 antigen-recognition structure of human T cells and blocks the T cell effector function involved in allograft rejection.
All of these therapy methods have undesirable side effects. For example, the corticosteroids may cause decreased resistance to infection, painful arthritis, osteoporosis, and cataracts. The cytotoxic agents may cause anemia and thrombocytopenia, and sometimes hepatitis. The antilymphocyte globulins may cause fever, hypotension, diarrhea, or sterile meningitis and are very expensive. Cyclosporine may cause decreased renal function, hypertension, tremor, anorexia, elevated low-density lipoprotein levels. OKT3 may cause chills and fever, nausea, vomiting, diarrhea, rash, headache, photophobia, and occasional episodes of life-threatening acute pulmonary edema.
X-ray irradiation therapy is currently used in leukemia patients undergoing bone marrow transplantation to produce marrow aplasia. The method is also used for renal and cardiac transplant patients who have responded inadequately to pharmacologic immunosuppression. Local irradiation to the grafted kidney has also been used to treat rejection.
There are two types of allograft rejection, acute humoral rejection (hyperacute rejection) and acute cellular rejection (acute rejection). Hyperacute rejection is generally an overwhelming, irreversible process that occurs when organs are transplanted into recipients who have preformed cytotoxic antibodies against antigens of the donor allograft. No combination of immunosuppressive drugs is capable of reversing this rapid process.
In contrast, acute rejection responds to treatment with immunosuppressive agents. Clinical manifestations of acute rejection may include fever, graft swelling or tenderness, oliguria, and increases in BUN and serum creatinine levels.